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The Xbox Live Arcade version of the game offers three different game modes including Standard Uno, Partner Uno, and House Rules Uno. In Partner Uno, players sitting across from each other join forces to form a team, so that a win by either player is a win for the team. In House Rules Uno, the rules can be tweaked and customized to the player's preference.

The Xbox Live Arcade version of Uno offers multiplayer for up to four players through Xbox Live. Players can join or drop-out of in-progress games at any time, with computer players automatically taking over for any missing humans. The game supports the Xbox Live Vision camera, allowing opponents to view an image of the player (or whatever the camera is pointed at) while playing the game.

The Xbox Live Arcade version of Uno supports downloadable content through the Xbox Live Marketplace. This content takes the form of custom theme decks, which feature new visual appearances, sound effects, and game rules. Decks available for download from the Xbox Live Marketplace include:

Project Gotham Racing Uno: In this deck, the cards feature pictures of the cars seen in the Project Gotham Racing series of video games. The rule changes include a card called the "Gotham Live" card, which is based on the replay feature in Project Gotham Racing 3. This card allows a player to look at the hand of any of the other players as well as functioning as a normal wild card.

Kameo: Elements of Power Uno: A custom deck with artwork from Kameo: Elements of Power. In addition, a special play card allows a player to swap his or her entire hand with the hand of any other player in the game.

Uno 35th Anniversary: A special deck made to celebrate the 35th Anniversary of the first edition of Uno released in the United States in 1971. In this deck, there are specialty "35" cards. If a "35" card is played only a 3 or 5 of any color can be played.

Super Street Fighter II Turbo HD Remix: This deck commemorates the release of Super Street Fighter II Turbo HD Remix, it only has one background, and one music track. Additionally, a new card named "Hadouken" was added. When played, the targeted player must draw cards until they get a Skip or a Reverse card.